Method of assembling and filling a drug delivery device

ABSTRACT

An injector may include a container having a wall with an interior surface and a seal assembly with an interior surface, the interior surfaces of the wall and the seal assembly defining a closed sterile reservoir filled with a drug product. The injector may also include a fluid delivery system comprising a clean, unsheathed, rigid container needle having a point disposed only partially through the seal assembly in a storage state, and disposed through the interior surface of the seal assembly into the sterile reservoir in a delivery state. Further, the injection may include an actuator that is adapted to move the container needle from the storage state to the delivery state.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. Ser. No. 15/040,335, filed Feb. 10, 2016,which is a continuation of U.S. Ser. No. 14/350,687, filed Apr. 9, 2014,which is the U.S. National Stage of PCT/US12/59680, filed Oct. 11, 2012,which claims the benefit of priority of U.S. Provisional Application No.61/547,667, filed Oct. 14, 2011. The entirety of the foregoing isexpressly incorporated herein by reference.

BACKGROUND

This patent is directed to an injector and a method of assembling theinjector, and, in particular, to a prefilled injector and a method ofassembling the prefilled injector.

Injectors are used to deliver medical fluids, such as liquid drugs, to apatient. In particular, the injector will provide the fluid to thepatient through a needle, cannula or catheter that defines a flow pathinto the patient. Certain injectors have a reservoir that is assembledby the manufacturer already connected to the flow path. However, thesereservoirs are typically provided empty by the manufacturer to thepatient or healthcare provider (e.g., doctor, nurse, healthcareassistant, etc.), and then the reservoir is filled at the time of use.Alternatively, the injector may be used in combination with a reservoirthat is provided to the patient or healthcare provider prefilled.

In either case, the injector must be prepared prior to use. For example,if the reservoir is provided empty, then the reservoir must be filled.To do this, a syringe is filled with the drug to be delivered, and thenthe drug is injected into the reservoir through an inlet port. Prior tothe injection, the inlet port must be sterilized by swabbing the outersurface with an alcohol wipe, for example. Similarly, before theprefilled reservoir is connected to the flow path in the alternativeinjector, the mating connectors must be sterilized, by swabbing thesurface with an alcohol wipe.

In either event, the use of the injector requires additional materialand time.

As set forth in more detail below, the present disclosure sets forth animproved injector embodying advantageous alternatives to theconventional devices and methods discussed above.

SUMMARY

According to an aspect of the present disclosure, an injector mayinclude a container having a wall with an interior surface and a sealassembly with an interior surface, the interior surfaces of the wall andthe seal assembly defining a closed sterile reservoir filled with a drugproduct. The injector may also include a fluid delivery systemcomprising a clean, unsheathed, rigid container needle having a pointdisposed only partially through the seal assembly in a storage state,and disposed through the interior surface of the seal assembly into thesterile reservoir in a delivery state. Further, the injection mayinclude an actuator that is adapted to move the container needle fromthe storage state to the delivery state.

The wall of the container may be a rigid wall or a flexible wall.

According to any of the foregoing, the seal assembly may be a flexibleunitary wall having an interior surface that defines the interiorsurface of the seal assembly. The flexible unitary wall may define aseptum disposed across the opening and fixedly attached to the wall ofthe container. Alternatively, the wall of the container may define abore, and the unitary flexible wall may define a stopper that ismoveable along the bore. In such a case, the wall of the container maydefine a closed end opposite the stopper and an open end in which thestopper is disposed. As a further alternative, the wall of the containermay define a bore with an opening in fluid communication with a firstend of the bore, and the unitary flexible wall defines a septum disposedacross the opening and fixedly attached to the wall of the container,the container further comprising a stopper that is disposed within asecond end of the bore and is moveable along the bore.

In the alternative to the preceding paragraph, the seal assembly mayinclude a flexible wall with an interior surface that defines theinterior surface of the seal assembly, and a clean barrier disposedexterior of the flexible wall to define an enclosed clean space betweenthe flexible wall and the clean barrier, the point of the containerneedle disposed through the clean barrier into the clean space in thestorage state. The wall of the container may define a bore, and theflexible wall and the clean barrier may each define a stopper that ismoveable along the bore. In addition, the container may include a ventin fluid communication with the space between the clean barrier and theflexible wall, which vent may be formed in the clean barrier or withinthe interior surface of the wall of the container. Further, the wall ofthe container may define a closed end opposite the stoppers and an openend in which the stoppers are disposed. In the alternative, the wall ofthe container may define a bore with an opening in fluid communicationwith a first end of the bore, and the flexible wall and the cleanbarrier each may define a septum disposed across the opening, thecontainer further including a stopper that is disposed within a secondend of the bore and is moveable along the bore.

According to any of the foregoing, the fluid delivery system may includeclean flexible tubing connected at a first end to the rigid containerneedle and a second end to a clean rigid injection needle receivedwithin a clean cover that closes off the clean rigid injection needle.

According to any of the foregoing, the actuator may be adapted to movethe container needle repeatedly between the storage state and thedelivery state.

According to any of the foregoing, the actuator may be adapted to delaymovement of the container needle from the storage state to the deliverystate after an input is received.

According to any of the foregoing, the injector may include amechanical, electro-mechanical, or electrical input device coupled tothe actuator.

According to any of the foregoing, the drug product may include a volumeof an erythropoiesis stimulating agent, a granulocyte colony-stimulatingfactor, a TNF blocker, a pegylated granulocyte colony-stimulatingfactor, interleukin-receptor specific antibody, IGF-receptor (InsulinGrowth Factor receptor) specific antibody, TGF-specific antibody, orPCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)-specific antibody.

According to another aspect of the present disclosure, a method ofassembling an injector may include filling a sterile reservoir of acontainer with a drug product under sterile conditions, the reservoirdefined by an interior surface of a wall of the container and aninterior surface of a seal assembly. The method may also includeinserting a point of a clean, unsheathed, rigid container needlepartially through the seal assembly under clean room conditionssubsequent to filing the sterile reservoir to define a storage state,and attaching the container needle to an actuator under clean roomconditions, the actuator adapted to move the container needle from thestorage state to a delivery state wherein the container needle isdisposed through the interior surface of the seal assembly into thesterile reservoir.

According to this aspect, the wall of the container may be a rigid wallor a flexible wall.

BRIEF DESCRIPTION OF THE DRAWINGS

It is believed that the disclosure will be more fully understood fromthe following description taken in conjunction with the accompanyingdrawings. Some of the figures may have been simplified by the omissionof selected elements for the purpose of more clearly showing otherelements. Such omissions of elements in some figures are not necessarilyindicative of the presence or absence of particular elements in any ofthe exemplary embodiments, except as may be explicitly delineated in thecorresponding written description. None of the drawings are necessarilyto scale.

FIG. 1 is a cross-sectional view of an embodiment of an injectoraccording to the present disclosure, with a unsheathed, rigid containerneedle in a storage state wherein the needle partially penetrates aunitary wall of the container;

FIG. 2 is a perspective view of a jig used with the container of theinjector of FIG. 1 to control the penetration of the flexible unitarywall of the container by the container needle;

FIG. 3 is a cross-sectional view of the injector of FIG. 1, with thecontainer needle in a delivery state wherein the needle penetrates theunitary wall of the container such that it is disposed through aninterior surface of the flexible wall into a sterile reservoir;

FIG. 4 is a schematic of a manufacturing facility wherein injectorsaccording to the present disclosure may be filled and assembled;

FIG. 5 is a cross-sectional view of an alternative embodiment of aninjector according to the present disclosure, with a unsheathed, rigidcontainer needle in a storage state wherein the needle partiallypenetrates a unitary wall of the container;

FIG. 6 is a cross-sectional view of a further alternative embodiment ofan injector according to the present disclosure, with a unsheathed,rigid container needle in a storage state wherein the needle partiallypenetrates a unitary wall of the container;

FIG. 7 is a cross-sectional view of an embodiment of an injectoraccording to the present disclosure, with a rigid container needle in astorage state wherein the needle partially penetrates a clean barrier,but not a flexible wall, of a seal assembly;

FIG. 8 is a cross-sectional view of an alternative embodiment of aninjector according to the present disclosure, with a rigid containerneedle in a storage state wherein the needle partially penetrates aclean barrier, but not a flexible wall, of a seal assembly;

FIG. 9 is a cross-sectional view of a variant to the embodiment of FIG.8 including vents to evacuate a clean space between a flexible wall andan exteriorly disposed clean barrier as an associated container needleis moved between a storage state and a delivery state;

FIG. 10 is a cross-sectional view of an additional variant to theembodiment of FIG. 8 including bypasses to evacuate a clean spacebetween a flexible wall and an exteriorly disposed clean barrier as anassociated container needle is moved between a storage state and adelivery state;

FIG. 11 is a cross-sectional view of the container of FIG. 10 in anintermediate state with the bypasses in fluid communication with a cleanspace defined between a flexible wall and a clean barrier;

FIG. 12 is a schematic view of further assembly of container and fluiddelivery system that may be used to preserve a sterile condition withinthe container;

FIG. 13 is a cross-sectional view of an injector according to a stillfurther embodiment of the present disclosure where a sterile conditionis maintained in a reservoir until actuation of the fluid deliverysystem;

FIG. 14 is a cross-sectional view of a variant of the injectorillustrated in FIG. 13;

FIG. 15 is a cross-sectional view of a further variant of the injectorillustrated in FIG. 13; and

FIG. 16 is a flowchart illustrating a method of assembling an injectoraccording to the present disclosure.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

Although the following text sets forth a detailed description ofdifferent embodiments of the invention, it should be understood that thelegal scope of the invention is defined by the words of the claims setforth at the end of this patent. It should also be understood that,unless a term is expressly defined in this patent using the sentence “Asused herein, the term ‘______’ is hereby defined to mean . . . ” or asimilar sentence, there is no intent to limit the meaning of that term,either expressly or by implication, beyond its plain or ordinarymeaning, and such term should not be interpreted to be limited in scopebased on any statement made in any section of this patent (other thanthe language of the claims). To the extent that any term recited in theclaims at the end of this patent is referred to in this patent in amanner consistent with a single meaning, that is done for sake ofclarity only so as to not confuse the reader, and it is not intendedthat such claim term be limited, by implication or otherwise, to thatsingle meaning. Finally, unless a claim element is defined by recitingthe word “means” and a function without the recital of any structure, itis not intended that the scope of any claim element be interpreted basedon the application of 35 U.S.C. § 112, sixth paragraph.

The detailed description is to be construed as exemplary only and doesnot describe every possible embodiment of the invention becausedescribing every possible embodiment would be impractical, if notimpossible. Numerous alternative embodiments could be implemented, usingeither current technology or technology developed after the filing dateof this patent, which would still fall within the scope of the claimsdefining the invention. Along these lines then, several embodimentsaccording to the present disclosure are illustrated in FIGS. 1-3 and5-15.

In general terms, an injector according to the present disclosureincludes a container, a fluid delivery system and an actuator. Whilereference is made to an injector, which in some instances may refer to adelivery device that ensures that a set volume of drug product isdelivered, it will be understood that this disclosure also encompassesinfusion devices, which in some instances may refer to a delivery devicethat ensures that a particular rate of delivery is achieved. It shouldalso be understood that the terms injector and infuser may be usedinterchangeably when referring to embodiments in the specification.

As illustrated in FIGS. 1-3 and 5-11, the container may include a wallwith an interior surface and a seal assembly with an interior surface,the interior surfaces of the wall and the seal assembly defining aclosed sterile reservoir filled with a drug product. Moreover, the fluiddelivery system illustrated in these embodiments may include a clean,unsheathed, rigid container needle having a point disposed onlypartially through the seal assembly in a storage state, and disposedthrough the interior surface of the seal assembly into the sterilereservoir in a delivery state. The injector may also include an actuatorthat is adapted to move the container needle from the storage state tothe delivery state, which may involve movement of the needle relative tothe container or of the container relative to the needle, as isdiscussed in greater detail below.

As is illustrated in FIGS. 1, 3, and 4-6, the seal assembly may be aflexible unitary wall having an interior surface that defines theinterior surface of the seal assembly, and the point of the containerneedle may be disposed partially into the unitary wall. Alternatively,as illustrated in FIGS. 7-11, the seal assembly may include a flexiblewall with an interior surface that defines the interior surface of theseal assembly, and a clean barrier disposed exterior of the flexiblewall to define an enclosed clean space between the flexible wall and theclean barrier. According to such embodiments, the point of the containerneedle is disposed through the clean barrier into the clean space in thestorage state.

Still further alternatives will be discussed in the context of each ofthe embodiments illustrated herein.

Referring then to FIG. 1, an injector 100 is illustrated therein. Theinjector 100 includes a container 102, a fluid delivery system 104, andan actuator 106.

The container 102 (which also may be referred to as a cartridge herein)includes a wall 110 with an interior surface 112 and an exterior surface114. While a unitary (i.e., one-piece) wall 110 has been illustrated inFIG. 1 that defines both the interior and exterior surfaces 112, 114, itwill be understood that according to other embodiments the wall 110 mayinclude a plurality of layers with different layers defining theinterior and exterior surfaces 112, 114.

According to certain embodiments of the present disclosure, the wall 110is rigid. According to other embodiments, the wall 110 may be flexible,whether according to the nature of the material that defines the wall oraccording to the nature of the structure of wall (e.g., a bellowsconstruction). The wall 110 may be made of glass, metal, or polymer, forexample. In particular, polymer versions may be made of polycarbonate,polypropylene, polyethylene (such as high density polyethylene),polytetrafluoroethylene, cyclic olefin polymer, cyclic olefin copolymer,Crystal Zenith olefinic polymer (available from Daikyo Seiko, Ltd.,Japan), nylon, or engineering resins, for example. As to flexibleversions of the wall 110, butyl rubber, silicon-based rubber,latex-based rubber, coated rubber, as well as multi-layer polymer films,such as may include polyethylene (such as low density polyethylene) andpolypropylene, may be used.

The wall 110 may have a generally cylindrical shape, which a shoulder120 separating a first cylindrical section 122 having a firstcross-sectional diameter from a second cylindrical section 124 having asecond cross-sectional diameter, the first cross-sectional diameterbeing smaller than the second cross-sectional diameter. The wall 110 mayalso define two opposed, open ends 126, 128. The wall 110, or moreparticularly the interior surface 112 of the wall 110, may also define abore 130.

The container 102 may include a flexible unitary wall 140 (which mayalso be referred to as a seal or septum) having an interior surface 142and an exterior surface 144. The wall 140 may be disposed in the firstopen end 126 defined by the wall 110 and fixedly attached to the wall110 of the container 102 such that there is limited relative movementbetween the wall 140 and the wall 110, for example at the points ofattachment of the wall 140 to the wall 110 across the open end oropening 126. Moreover, the interior surfaces 112, 142 of the wall 110and the flexible wall 140 may define, at least in part, a closed sterilereservoir 150 that is filled with a drug product 160, described ingreater detail below. The wall 140 may be made of bromobutyl,chlorobutyl, or chlorobromobutyl rubber, fluoropolymer rubber, naturalrubber, silicon-based rubber, silicon, or santoprene, for example.

The container 102 may also include a stopper or piston 170 with interiorand exterior surfaces 172, 174. The piston 170 may be received withinthe end 128 defined by the wall 110, and may be moveable along the bore130 between the ends 126, 128 of the container 102. According to such anembodiment, the reservoir 150 within which the drug product 160 isdisposed may be defined by the interior surfaces 112, 142, 172 of thewalls 110, 140 and piston 170.

The container 102 may be used in conjunction with the fluid deliverysystem 104, the relevant portions of which are illustrated in FIG. 1. Inparticular, the fluid delivery system 104 may include a clean,unsheathed, rigid container needle 180 having a point 182. Asillustrated, the point 182 is disposed only partially into the flexiblewall 140 in a storage state. The penetration of the point 182 of theneedle 180 into the wall 140 may be controlled through a number ofmethods and/or mechanisms. For example, FIG. 2 illustrates a jig thatmay be used in combination with the container 102 to control the depthto which the point 182 penetrates the wall 140.

The fluid delivery system 104 may also include an injection needle 190with a point 192. The point 192 of the injection needle 190 may becovered with a needle shield 194 to prevent contact with andcontamination of the point 192. The container needle 180 and theinjection needle 190 may be connected by a cannula or tube 200, whichmay be a flexible cannula according to certain embodiments of thepresent disclosure. The needle 190, like the needle 180, may be made ofstainless steel, for example.

Fluid delivery system 104 may be used in conjunction with the actuator106, mentioned previously and illustrated schematically in FIG. 1. Theactuator 106 may be adapted to move the container needle 180 between thestorage state illustrated in FIG. 1 and a delivery state illustrated inFIG. 3. In the delivery state, the container needle 180 is disposedthrough the interior surface 142 of the flexible wall 140 into thesterile reservoir 150.

The movement of the needle 180 between the states may occur in a varietyof fashions. For example, the needle 180 may be held fixed relative tothe housing of the injector 100, and the container 102 may move relativeto the needle 180 and the housing. Alternatively, the container 102 maybe held fixed relative to the housing, and the needle 180 may be movedrelative to the container 102 and the housing. It may also be possiblefor both container 102 and needle 180 to move relative to the housing ofthe injector 100. It will be understood that all of these actions may beembraced within the statement that the actuator 106 is adapted to movethe container needle 180 between the storage and delivery states.

The actuator 106 may be mechanical, electro-mechanical, or electrical.For example, the actuator 106 may include a solenoid, motor-drivenlever, motor with associated gearing, etc. It may even be possible toprovide a tab or button attached to the container 102 or the needle 180to permit the user to achieve the relative motion between the container102 and the needle 180 manually. In fact, the container 102 may bereceived within a tab or button that is depressed into the housing whenthe injector 100 is activated to move the container 102 relative to the(fixed) needle 180.

The actuator 106 may move the container needle 180 between storage anddelivery states by moving the needle 180 from the storage state to thedelivery state, or by moving the needle 180 from the delivery state tothe storage state. In fact, the actuator may move the container needle180 between the storage and delivery states repeatedly (i.e., multipletimes or repetitions). Furthermore, the actuator 106 may move thecontainer needle 180 immediately upon receipt of an input or signal(e.g., as generated through the depression or manipulation of a button,switch or other input device, which may be mechanical,electro-mechanical or electrical in nature, coupled to the actuator106), or may delay movement of the container needle 180 between storageand delivery states some period of time after an input is received.According to a particular embodiment, the actuator 106 may delaymovement of the needle 180 from the storage state to the delivery stateuntil after such a time delay.

As mentioned previously, the reservoir 150 is described as sterile,while the container needle 180 is described as clean. These termsdescribe the condition of the reservoir 150 or the needle 180 as aconsequence of their assembly under conditions that will ensure aspecified level of freedom from contamination, wherein a sterile objector device is understood to have a relatively higher level of freedomfrom contamination than a clean object or device. By way of non-limitingexample, the concepts of sterility and cleanliness may be discussed withreference to the schematic of FIG. 4, which discussion will berecognized applies not only to the embodiment illustrated in FIGS. 1 and3, but all of the embodiments described herein.

FIG. 4 illustrates a manufacturing facility 250, and may be used todiscuss a manufacturing process that is conducted within the facility250. It will be noted that the facility 250 is divided into a pluralityof spaces 252, 254, 256, 258, 260, 262, 264, 266, 268, which divisionsmay be maintained through the use of permanent or semi-permanent wallsor other barriers. As will be understood, certain spaces or regions maybe divided without barriers or walls, but may simply be separated on anorganizational level instead. Additionally, it will be recognized that agreater or lesser number of spaces or an alternative arrangement of thespaces may be used, such differing numbers or arrangements of spacesbeing readily determinable by one of ordinary skill in the art.

The components of the container 102 (walls 110, 140, and stopper/piston170) would enter the facility 250 through space 252, wherein thecomponents are sterilized using e-beam technology, for example.Alternatively, the container components may be sterilized through othercurrently-known (e.g., treatment with chlorine dioxide or vapor phasehydrogen peroxide) or later-developed sterilization procedures as thecomponents enter the facility 250 at entry points 252, 264, 266. Thecontainer 102 would then pass into space 254 for filing with the drugproduct. The space 254 may be operated as an aseptic Class 100 cleanroom. A Class 100 clean room is one in which the number of particles ofsize 0.5 μm or larger permitted per cubic foot of air is less than 100.Once the fill has been performed and the stopper 170 has been disposedin the end 128 of the container 102, the container 102 and drug product160 is moved through transfer space 256 (also operated as a Class 100clean room, wherein certain embodiments are also aseptic) before beingreceived within storage space 258.

The containers 102 move from the storage space 258 into inspection area260 (aseptic in certain embodiments), wherein the containers 102 areinspected prior to assembly with the fluid delivery system 104, actuator106 and other elements of the injector 100. Because the drug product 160is contained within the sealed container 102 at this point, theinspection area may be operated as a Class 10,000 clean room. Onceinspected, the prefilled, sterile container 102 may be passed frominspection space 260 to assembly space 262.

Similar to the inspection space 260, the assembly space 262 may beoperated as an aseptic Class 10,000 clean room. Materials being passedinto the clean room from spaces 264, 266 may be in a sterile condition,or may be sterilized using e-beam technology, for example. Within theassembly space 262, the fluid delivery system 104 is connected to thecontainer 102 once the surface 144 of the wall/septum 140 has beensterilized by swabbing the surface 144 with an alcohol wipe, forexample. Because of the lower level of cleanliness, the fluid deliverysystem 104 may be referred to as clean, but not necessarily as sterile.However, because the container needle 180 does not penetrate through thewall 140, the reservoir 150 and the drug product 160 remains sterile(i.e., at the higher level of cleanliness). The remainder of theinjector 100 may also be assembled in this space 262 prior to theinjector 100 passing into the packaging space 268, with certain aspectsof the injector (e.g., the actuator 106) potentially being assembledwith the container 102 or the fluid delivery system 104 prior to theassembly of the container 102 and the fluid delivery system 104.

It will be recognized that the embodiment of the injector 100illustrated in FIGS. 1 and 3 is simply an exemplary embodiment accordingto the present disclosure. To this end, FIGS. 5 and 6 illustratevariants of the injector illustrated in FIGS. 1 and 3.

According to the embodiment of FIG. 5, the injector 300 includes acontainer 302, a fluid delivery device 304 and an actuator 306. Similarto the embodiment of FIGS. 1 and 3, the container 302 includes a wall310 with interior and exterior surfaces 312, 314. Moreover, the wall 310may have two opposed ends 320, 322 with the interior surface 312 of thewall 310 defining a bore 324 between the opposing ends 320, 322.

However, unlike the container 102, the container 302 has a fixed plug326 that closes the end 320. In addition, while the container 302 has aflexible unitary wall 330 with interior and exterior surfaces 332, 334,the wall 330 is disposed within the end 322 of the container 302, andthus performs the role of the stopper/piston 170 in the container 102.Consequently, the wall 330 is moveable along the bore 324 between theopposing ends 320, 322. Moreover the interior surfaces 312, 332 of thewalls 310, 330 define a sterile reservoir 340 in which a drug product350 is disposed.

According to this embodiment, the fluid delivery device 304 may includea clean, unsheathed, rigid container needle 360 having a point 362. Thepoint 362 of the needle 360, like the point 182 of the needle 180, isdisposed only partially into the flexible wall 330 in a storage state,with the actuator 306 causing the point 362 to move between the storagestate and a delivery state wherein the point 362 is disposed through theinterior surface 332 of the flexible wall 330 into the sterile reservoir340. The container needle 360 may be in fluid communication with ainjection needle 370 having a point 372 covered with a shield 374through a cannula 380 received within a piston rod 382, for example,which rod 382 may be used to move the stopper/piston 330 between theends 320, 322 of the container 302.

FIG. 6 shows a closely related variant to that illustrated in FIG. 5.According to the variant illustrated in FIG. 6, a container has a wall390 with interior and exterior surfaces 392, 394. However, unlike thecontainers discussed previously, the wall 390 defines a closed end 396and an open end 398. The container also includes a flexible wall 400,like the wall 330 of the embodiment of FIG. 5, which wall 400 ismoveable within the container between the open end 398 and the closedend 396. According to this embodiment, a separate structure is notrequired to close off one of the ends 396, 398 because the wall 390already defines the closed end 396 itself. For that matter, the closedend 396 may be resized so that it is radially larger than illustrated inFIG. 6.

Having thus discussed a plurality of embodiments wherein a seal assemblyincludes only a flexible unitary wall, a further plurality ofembodiments will be discussed with reference to FIGS. 7-11 wherein theseal assembly includes a plurality of walls and/or seals. This structuremay also be referred to as a compartmentalized seal (or septum withreference to FIG. 7, or stopper with reference to FIGS. 8-11).

Referring first to FIG. 7, an injector 450 includes a container 452, afluid delivery system 454, and an actuator 456.

The container 452 includes a wall 460 with an interior surface 462 andan exterior surface 464. Like the container of FIGS. 1 and 2, the wall460 may have a generally cylindrical shape, with a shoulder 470separating a first cylindrical section 472 having a firstcross-sectional diameter from a second cylindrical section 474 having asecond cross-sectional diameter, the first cross-sectional diameterbeing smaller than the second cross-sectional diameter. The wall 460 mayalso define two opposed, open ends 476, 478. The wall 460, or moreparticularly the interior surface 462 of the wall 460, may also define abore 480.

Unlike the container 102 of FIGS. 1 and 3, the container 452 of FIG. 7has a seal assembly that includes more than a single, unitary wall. Theseal assembly of the container 452 includes a flexible wall 490 and aclean barrier 492. The flexible wall 490 has an interior surface 494 andan exterior surface 496, while the clean barrier 492 has an interiorsurface 498 and an exterior surface 500. The interior surfaces 462, 494of the wall 460 and the flexible wall 490 defining a closed sterilereservoir 510 filled with a drug product 520. On the other hand, theclean barrier 492 is disposed exterior of the flexible wall 490 todefine an enclosed clean space 530 between the flexible wall 490 and theclean barrier 492. The clean space 530 may be defined by the interiorsurface 462 of the wall 460, the exterior surface 496 of the flexiblewall 490, and the interior surface 498 of the clean barrier 492.

As illustrates, the container 452 may also include a stopper or piston540 with interior and exterior surfaces 542, 544. The piston 540 may bereceived within the end 478 defined by the wall 460, and may be moveablealong the bore 480 between the ends 476, 478 of the container 452.According to such an embodiment, the reservoir 510 within which the drugproduct 520 is disposed may be defined by the interior surfaces 462,494, 542 of the walls 460, 490 and piston 540.

The embodiment of FIG. 7 also includes the fluid delivery system 454comprising a clean, unsheathed, rigid container needle 550 having apoint 552 disposed through the clean barrier 492 into the clean space530 in a storage state, and disposed through the interior surface 494 ofthe flexible wall 490 into the sterile reservoir 510 in a deliverystate. In this sense, the container needle 550 only partially penetratesthe seal assembly. The fluid delivery system 454 may also include aninjection needle 560 with a point 562 covered at least initially with aneedle shield 564 to prevent contact with and contamination of the point562. The container needle 550 and the injection needle 560 may beconnected by a cannula or tube 570, which may be a flexible cannulaaccording to certain embodiments of the present disclosure.

As was the case with the embodiment of FIGS. 1 and 3, the presentdisclosure includes a number of variants for the embodiment illustratedin FIG. 7, which variants are illustrated in FIGS. 8-11.

The embodiment of FIG. 8 is similar to the embodiment of FIG. 7 in theway that the embodiment of FIG. 5 was similar to that of FIGS. 1 and 3.In particular, the seal assembly of an injector 600 according to theembodiment of FIG. 8 is disposed in a container 602 in place of thestopper/piston 540 illustrated relative to the container 452. That is,the container 602 includes a wall 604 that defines a bore 606, and aflexible wall 608 and a clean barrier 610 each define a stopper that ismoveable along the bore 606. While the wall 604 of the container 602does not define opposing open and closed ends in the embodimentillustrated, such an alternative is possible according to the presentdisclosure similar to FIG. 6.

FIGS. 9-11 illustrate variants to the embodiment illustrated in FIG. 8,which variants include additional features to permit the space or regionbetween the flexible wall and the clean barrier to be evacuated orexhausted. These additional features may be referred to as vents, valvesor bypasses, but all of these structures permit gases to escape from thespace or region between the flexible wall and the clean barrier when anactuator moves the associated container needle from a storage state to adelivery state. This is not to suggest that the inner wall and exteriorbarrier cannot remain separated, for example through the use of a spaceror spacers, according to other embodiments of the present disclosure.However, the alternatives of FIGS. 9-11 illustrate options forevacuating the clean space as to those embodiments where the inner walland exterior barrier come together.

A container 650 is illustrated in FIG. 9 including a wall 652 and a sealassembly, the assembly including a flexible wall 654 and a clean barrier656. The flexible wall 654 has an interior surface 658 and an exteriorsurface 660, while the clean barrier 654 has an interior surface 662 andan exterior surface 664. An interior surface 668 of the wall 652 and theinterior surface 658 of the flexible wall 654 defining a closed sterilereservoir 670 filled with a drug product 680. On the other hand, theclean barrier 656 is disposed exterior of the flexible wall 654 todefine an enclosed clean space 690 between the flexible wall 654 and theclean barrier 656. The clean space 690 may be defined by the interiorsurface 668 of the wall 652, the exterior surface 660 of the flexiblewall 652, and the interior surface 662 of the clean barrier 656.

As is also illustrated in FIG. 10, a fluid delivery system 700 includinga container needle 702 is used in conjunction with the seal assembly.The container needle 702 is illustrated in the storage state, whereinthe container needle 702 is disposed through the clean barrier 656 sothat a point 704 of the needle 702 is disposed in the clean space 690.The point 704 will penetrate the flexible wall 654 and depend into thereservoir 670 in a delivery state, not shown. It will be recognized thatthe needle 702 is not drawn to scale particularly as to its length, asis true of other embodiments illustrated here.

In contrast with the previously discussed embodiments, the container 650illustrated in FIG. 9 includes at least one vent 710. The vents 710 arein fluid communication with the clean space 690 between the cleanbarrier 656 and the flexible wall 654. The vents 710 are selectivelyactuated to permit gas trapped between the clean barrier 656 and theflexible wall 654 to escape through the vents 710 when the seal assemblyis moved between the illustrated storage state and the delivery state,wherein the clean barrier 656 is advanced in the direction of theflexible wall 654 to permit the point 704 of the container needle 702 topenetrate through the wall 654. However, the vents 710 may be in asealed condition relative to the environment until actuated, forexample, by a change in the pressure within the clean space 690.

As illustrated, the vents 710 are disposed within the clean barrier 656,and extend between the interior surface 662 and the exterior surface 664of the barrier 656. A flap 712 covers the end of the vent 710 proximateto the exterior surface 664, and thereby seals the end of the vent 710until the vent is actuated, preserving the cleanliness of the space 690between the clean barrier 656 and the flexible wall 654. Alternatively,the vents 710 may be arranged, for example, in the wall 652 of thecontainer 650.

FIGS. 10 and 11 illustrate a further variant on the system of FIG. 8,wherein a container 720 includes a wall 722 and a seal assembly, theassembly including a flexible wall 724 and a clean barrier 726. Theflexible wall 724 has an interior surface 728 and an exterior surface730, while the clean barrier 726 has an interior surface 732 and anexterior surface 734. An interior surface 738 of the wall 722 and theinterior surface 728 of the flexible wall 724 define a closed sterilereservoir 740 filled with a drug product 750. On the other hand, theclean barrier 726 is disposed exterior of the flexible wall 724 todefine an enclosed clean space 760 between the flexible wall 724 and theclean barrier 726. The clean space 760 may be defined by the interiorsurface 738 of the wall 722, the exterior surface 730 of the flexiblewall 722, and the interior surface 732 of the clean barrier 726.

As is also illustrated in FIG. 10, a fluid delivery system 770 includinga container needle 772 is used in conjunction with the seal assembly.The container needle 772 is illustrated in the storage state, whereinthe container needle 772 is disposed through the clean barrier 726 sothat a point 774 of the needle 772 is disposed in the clean space 760.The point 774 will penetrate the flexible wall 724 and depend into thereservoir 740 in a delivery state, not shown.

In contrast with the previously discussed embodiments, the container 720illustrated in FIG. 10 includes at least one bypass or vent 780. Thebypasses 780 are in fluid communication with the reservoir 740. Thebypasses 780 are selectively actuated to permit gas trapped between theclean barrier 726 and the flexible wall 724 to escape through thebypasses 780 into the reservoir 740 when the seal assembly is movedbetween the illustrated storage state and the delivery state, whereinthe clean barrier 726 is advanced in the direction of the flexible wall724 to permit the point 774 of the container needle 772 to penetratethrough the wall 724.

However, the bypasses 780 are not in fluid communication with the cleanspace 760 until the flexible wall 724 has moved from the storage stateillustrated in FIG. 10 to an intermediate state illustrated in FIG. 11.As illustrated in FIGS. 10 and 11, the bypasses 780 may be defined inthe interior surface 738 of the wall 722, and as illustrated may takethe form of a groove 782 formed in the wall 722. The groove 782 may havea distal end 784 and a proximal end 786. As will be recognized, untilthe exterior surface 730 of the flexible wall 724 moves past the distalend 784 of the grooves 782, the reservoir 740 is in a sealed conditionrelative to the clean space 760. However, once the exterior surface 730of the flexible wall 724 moves past distal end 784 of the grooves 782,the gases trapped between the clean barrier 726 and the flexible wall724 may exhaust into the reservoir 740. This may facilitate the movementof the barrier 726 and needle 770 toward the flexible wall 724.

While all of the forgoing embodiments have focused to one degree oranother on a fluid delivery system partially disposed through a sealassembly, there are other alternatives where the container needle is notdisposed through the seal assembly, or where the container needle isdisposed fully through the seal assembly. Three such alternatives areillustrated in FIGS. 12-14.

FIG. 12 illustrates an injector 800 with a container 802, a fluiddelivery system 804 and an actuator 806. Similar to the embodimentsillustrated above, the actuator 806 would cause the fluid deliverysystem 804 to be disposed through a seal assembly associated with thecontainer 802 in a delivery state, and thereby be in fluid communicationwith the interior of the container 802. However, as mentioned above, inthe storage state illustrated in FIG. 12, the fluid delivery system isnot even partially disposed through the seal assembly.

To this end, the container 802 includes at least a flexible wall 810,which may be in the form of a septum or a stopper according to thepresent disclosure. The flexible wall 810 has an interior surface 812and an exterior surface 814. Additionally, the fluid delivery system 804includes a container needle 816, an injection needle 818, and a flexibleconduit 820 connecting the container needle 816 and the injection needle818. Both the container needle 816 and the injection needle 818 arereceived within a cover 822, 824 that preserves the cleanliness of theneedle 816, 818. The cover 822 may be referred to as a cap, while thecover 824 may be referred to as a shield. Also included is an alcoholwipe 826 disposed between the flexible wall 810 and the cover 822, whichwipe 826 may be kept in an air-tight condition to maintain alcoholsaturation.

According to the present disclosure, prior to initiating action of theactuator 806, the wipe 826 is drawn out from between the flexible wall810 and the cover 822. For example, an end of the wipe 826 may bedisposed outside housing of the injector 800 to permit the end to begrasped and the wipe 826 pulled out from the injector 800.Alternatively, the end of the wipe 826 may be attached to another aspectof the injector 800, such as a liner that covers an adhesive surface ofthe injector 800 that will be attached to the patient, such that whenthe liner is removed to expose the adhesive surface, the wipe 826 ispulled out from the injector 800 as well. The removal of the wipesterilizes surface 814 of the wall 810 and opposing surface 828 of thecap 822. The actuator 806 then moves the container needle 816 throughthe cap 822 and the flexible wall 810.

FIGS. 13 and 14, on the other hand, illustrated embodiments wherein thecontainer needle is disposed through the flexible wall (defining thestopper or septum) and a valve is used to seal the reservoir off fromthe injection needle. The valve may also be used to control the flow ofdrug product from the reservoir in the container. In this fashion, thevalve may be used to meter an amount of drug product from the reservoir,or to delay the flow of the drug product until a time delay has elapsedrelative to receipt of an input from an input device (e.g., button orswitch), for example.

As such, FIG. 13 illustrates an injector 850 with a container 852, afluid delivery system 854 and an actuator 856. The container 852includes at least a flexible wall 860, which may be in the form of aseptum according to the illustrated embodiment. The flexible wall 860has an interior surface 862 and an exterior surface 864. Additionally,the fluid delivery system 854 includes a container needle 866, aninjection needle 868, and a flexible cannula or tubing 870 connectingthe container needle 866 and the injection needle 868. The injectionneedle 868 may be received within a cover 872 that preserves thecleanliness of the needle 868.

On the other hand, the container needle 866 (and in particular a point874 of the container needle 866) is disposed through the flexible wall860 through the interior surface 862. The needle 866 is thus in fluidcommunication with a sterile reservoir 880 and a drug product 890disposed within the reservoir 880. Fluid communication between thecontainer needle 866 and the injection needle 868 is interrupted by avalve 900 disposed in or along the flexible tubing 870, which valve 900may define a boundary between the sterile portion of the injector 850and the clean portion of the injector 850. Thus, unlike the otherembodiments discussed above relative to FIGS. 1-12, the actuator 856 ofthe injector 850 is not used to move the container needle 866 relativeto the flexible wall 860, but instead to manipulate the valve between aclosed state wherein fluid communication is interrupted between theneedles 866, 868 and an open state wherein the container needle 866 isin fluid communication with the injection needle 868.

It will be recognized that the valve 900 may take a variety of shapesand forms, two of which are illustrated in FIGS. 13 and 14. Inparticular, FIG. 13 illustrates an embodiment of the injector 850wherein a rotatable valve 900 is disposed in the flexible tubing 870, orhas an internal valve member that is in fluid communication with thefluid flow path defined between the container needle 866 and theinjection needle 868. FIG. 14, by contrast, illustrates and embodimentof the injector wherein a pinch valve 902 is disposed along the flexibletubing 870, and thus cooperates with an exterior surface of the tubing870 to interrupt the fluid communication between the container needle866 and the injection needle 868.

Embodiments such as are illustrated in FIGS. 13 and 14 would also workwell with a container that has a permanently attached needle, such thatthe container is in the form of a syringe, for example.

It will be further understood that the embodiments illustrated in FIGS.13 and 14 may be further modified to incorporate a seal assemblyincluding a plurality of walls and/or seals, such as is illustrated inFIG. 7, for example. FIG. 15 illustrates such an embodiment.

In particular, FIG. 15 illustrates an injector 920 with a container 922,a fluid delivery system 924, an actuator 926, and a seal assembly 928.The fluid delivery system 924 may include a container needle 930, aninjection needle 932, and a flexible cannula or tubing 934 connectingthe container needle 930 and the injection needle 932. The injectionneedle 932 may be received within a cover 936 that preserves thecleanliness of the needle 932. The needle 932 may also be in selectivefluid communication with a sterile reservoir 940 and a drug product 942disposed within the reservoir 940 via a valve 944 disposed in or alongthe flexible tubing 934. In this regard, the injector 920 is similar tothose illustrated in FIGS. 13 and 14.

However, the seal assembly 928 of the injector 920 also has a flexiblewall 950 and a clean barrier 952. The flexible wall 950 and the cleanbarrier 952 each have interior and exterior surfaces, with the interiorsurface of the flexible wall 950 defining, in part, the closed sterilereservoir 940. On the other hand, the clean barrier 952 is disposedexterior of the flexible wall 950 to define an enclosed clean space 954between the flexible wall 950 and the clean barrier 952 in which a point956 of the container needle 930 may be disposed.

In this regard, the embodiment of FIG. 15 has two potential barriers:one in the form of the valve 944 and a second in the form of theplacement of the point 956 within the clean space 954. In fact, thevalve 944 may be controlled to provide a delay in the injection of thedrug product 942 after the container needle 930 has been caused topenetrate trough the flexible wall 950 into the reservoir 940.

As will be recognized, the devices according to the present disclosuremay have one or more advantages relative to conventional technology, anyone or more of which may be present in a particular embodiment inaccordance with the features of the present disclosure included in thatembodiment. As one example, these embodiments maintain the sterility ofthe drug product until the time of use. As another example, thepotential for mixing of the drug product is limited or eliminated priorto the time of use. As a still further example, unintended delivery ofthe drug product is limited or prevented prior to the time of use.

For illustrative purposes only, FIG. 16 provides a further method 1000for assembling delivery devices according to any of the embodimentsdisclosed above. The method 1000 follows the general processing flowoutlined above relative to FIG. 4. However, rather than referring to thecleanroom classifications according to U.S. Federal Standard 209E,reference is made to cleanroom classifications according to the GMP EUstandard. Moreover, the method 1000 provides additional optional paths(represented as a left or right branch) that may be followed in theassembly of the delivery device. Consequently, the method 1000 of FIG.16 may be viewed as supplementary to the discussion above relative toFIG. 4.

The method 1000 for assembling delivery devices begins at block 1002.The containers used in the device are initially stored in sealed tubs.As mentioned above, these containers may be or may have been sterilizedat some point. At block 1002, the tubs are debagged, for example usingan automated debagger in a Grade C cleanroom. At block 1004, the Tyvekseal is peeled off (e.g., by a robot) and removed, for example, in aspace operated as a Grade A cleanroom, perhaps within an isolator in aspace otherwise operated a Grade C cleanroom.

The containers are filled and stoppers are attached, and then thecontainers are re-nested in open tubs, at block 1006, in a spaceoperated as a Grade A cleanroom, perhaps within an isolator in a spaceotherwise operated a Grade C cleanroom. From this point, two differentalternative paths, or branches, are possible.

The filled containers may be left in the open tubs at block 1008. Thetubs may be conveyed and carted to a storage space (e.g., cold room) atblock 1010.

If the route of block 1008, 1010 is followed, then the method 1000 maycontinue with the tubs being transferred for processing to an inspectionroom at block 1012. The filled containers are then denested from theopen tubs at block 1014, and supplied to an automated inspection machineat block 1016. Automated inspection of the filled containers occurs atblock 1016, followed by optional, additional semi-automated or manualinspection at block 1018.

Alternatively, the tubs may be resealed, rebagged, and labeled, at block1020. For example, the tubs may be resealed with Tyvek (e.g., using aBausch +Strobel tub sealer), rebagged, and then labeled in a Grade Ccleanroom at block 1020. The tubs may then be stored, or even shipped,if necessary, at blocks 1022, 1024.

Once storage or transport is completed, the tubs are debagged, forexample using an automated debagger at block 1026. At block 1028, theTyvek seal is peeled off and removed. The filled containers may then bedenested for inspection, at block 1030. The actions at blocks 1026,1028, 1030 are performed in a Grade C cleanroom. An automated inspectionmay then be carried out using a visual inspection machine designed foroperation in a Grade C cleanroom at block 1032.

Following either procedure, the filled, inspected containers may then betransferred to rondo trays at block 1034.

According to a first procedure, the rondo trays may be sent directly tostorage at block 1036. If the route of block 1036 is followed, then therondo trays are transferred for processing to the device assembly roomat block 1038. The containers are denested at block 1040, and assembledwith the other elements of the delivery device at block 1042 to definean assembled delivery device (e.g., an injector or an infuser).

Alternatively, the containers may be moved into tubs, which are sealed,bagged, and labeled, at block 1044. For example, the tubs may beresealed with Tyvek, bagged, and then labeled in a Grade C cleanroom.The tubs may then be stored, or even shipped for further processing, ifnecessary, at blocks 1046, 1048. Once storage or transport completed,the tubs are debagged, for example using an automated debagger at block1050. At block 1052, the Tyvek seal is peeled off and removed, and thecontainers are denested. The filled containers may then be assembledwith the other elements of the delivery device at block 1054. Theactions at blocks 1050, 1052, 1054 may all occur in a Grade C cleanroom.

In either event, the assembled devices are packaged at block 1056, andthe packaged, assembled devices are stored at block 1058. Finally, thepackaged, assembled devices are transported to the distributor, and/orfor other distribution actions at block 1060.

Other advantages not specifically listed herein may also be recognizedas well. Moreover, still other variants and alternatives are possible.

As an example, while the operation of the actuator has been described inregard to the foregoing embodiments as moving, for example, thecontainer needle from a storage state to a delivery state, it will beunderstood that the actuator may also move the container needle from thedelivery state to the storage state. For example, if a dose of drugproduct is to be delivered that is less than the volume of the reservoir(such as may be the case wherein the injector is designed to beprogrammed to deliver an adjustable dose according to the needs of thepatient (e.g., pediatric vs. adult patient)), then the actuator may movethe container needle from the storage state to the delivery state priorto delivery of the dose, and from the delivery state to the storagestate after delivery of the dose. The movement from the delivery stateto the storage state will in effect reseal the container and close thefluid path to the patient. This sequence of movement between the storagestate and the delivery state may be repeated. As noted above,maintaining a closed fluid path until delivery is initiated isadvantageous in that the opportunity for unintended delivery of the drugproduct to the patient and/or mixing of the drug product with thepatient's bodily fluids is reduced.

The injectors according to the present disclosure may be used with avariety of drug products, including colony stimulating factors, such asgranulocyte colony-stimulating factor (G-CSF), may be administered toincrease the number of immune cells (e.g., white blood cells) found inbone marrow or peripheral blood. Such G-CSF agents include, but are notlimited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).

In other embodiments, the injector may be used with various otherproducts including, for example, an erythropoiesis stimulating agent(ESA), which may be in a liquid or a lyophilized form. An ESA is anymolecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa),Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxypolyethylene glycol-epoetin beta), Hematide®, MRK-2578, INS-22,Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetinzeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetinalfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin®(epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetintheta, and epoetin delta, as well as the molecules or variants oranalogs thereof as disclosed in the following patents or patentapplications, each of which is herein incorporated by reference in itsentirety: U.S. Pat. Nos. 4,703,008; 5,441,868; 5,547,933; 5,618,698;5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422; 5,986,047;6,583,272; 7,084,245; and 7,271,689; and PCT Publ. Nos. WO 91/05867; WO95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO 2007/136752.

An ESA can be an erythropoiesis stimulating protein. As used herein,“erythropoiesis stimulating protein” means any protein that directly orindirectly causes activation of the erythropoietin receptor, forexample, by binding to and causing dimerization of the receptor.Erythropoiesis stimulating proteins include erythropoietin and variants,analogs, or derivatives thereof that bind to and activate erythropoietinreceptor; antibodies that bind to erythropoietin receptor and activatethe receptor; or peptides that bind to and activate erythropoietinreceptor. Erythropoiesis stimulating proteins include, but are notlimited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega,epoetin iota, epoetin zeta, and analogs thereof, pegylatederythropoietin, carbamylated erythropoietin, mimetic peptides (includingEMP1/hematide), and mimetic antibodies. Exemplary erythropoiesisstimulating proteins include erythropoietin, darbepoetin, erythropoietinagonist variants, and peptides or antibodies that bind and activateerythropoietin receptor (and include compounds reported in U.S. Publ.Nos. 2003/0215444 and 2006/0040858, the disclosures of each of which isincorporated herein by reference in its entirety) as well aserythropoietin molecules or variants or analogs thereof as disclosed inthe following patents or patent applications, which are each hereinincorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008;5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078;5,773,569; 5,955,422; 5,830,851; 5,856,298; 5,986,047; 6,030,086;6,310,078; 6,391,633; 6,583,272; 6,586,398; 6,900,292; 6,750,369;7,030,226; 7,084,245; and 7,217,689; US Publ. Nos. 2002/0155998;2003/0077753; 2003/0082749; 2003/0143202; 2004/0009902; 2004/0071694;2004/0091961; 2004/0143857; 2004/0157293; 2004/0175379; 2004/0175824;2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914; 2005/0026834;2005/0096461; 2005/0107297; 2005/0107591; 2005/0124045; 2005/0124564;2005/0137329; 2005/0142642; 2005/0143292; 2005/0153879; 2005/0158822;2005/0158832; 2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;2005/0202538; 2005/0227289; 2005/0244409; 2006/0088906; and2006/0111279; and PCT Publ. Nos. WO 91/05867; WO 95/05465; WO 99/66054;WO 00/24893; WO 01/81405; WO 00/61637; WO 01/36489; WO 02/014356; WO02/19963; WO 02/20034; WO 02/49673; WO 02/085940; WO 03/029291; WO2003/055526; WO 2003/084477; WO 2003/094858; WO 2004/002417; WO2004/002424; WO 2004/009627; WO 2004/024761; WO 2004/033651; WO2004/035603; WO 2004/043382; WO 2004/101600; WO 2004/101606; WO2004/101611; WO 2004/106373; WO 2004/018667; WO 2005/001025; WO2005/001136; WO 2005/021579; WO 2005/025606; WO 2005/032460; WO2005/051327; WO 2005/063808; WO 2005/063809; WO 2005/070451; WO2005/081687; WO 2005/084711; WO 2005/103076; WO 2005/100403; WO2005/092369; WO 2006/50959; WO 2006/02646; and WO 2006/29094.

Examples of other pharmaceutical products for use with the device mayinclude, but are not limited to, antibodies such as Vectibix®(panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); otherbiological agents such as Enbrel® (etanercept, TNF-receptor /Fc fusionprotein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim , G-CSF,hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such asSensipar® (cinacalcet). The device may also be used with a therapeuticantibody, a polypeptide, a protein or other chemical, such as an iron,for example, ferumoxytol, iron dextrans, ferric glyconate, and ironsucrose. The pharmaceutical product may be in liquid form, orreconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins setforth below, including fusions, fragments, analogs, variants orderivatives thereof:

OPGL specific antibodies, peptibodies, and related proteins, and thelike (also referred to as RANKL specific antibodies, peptibodies and thelike), including fully humanized and human OPGL specific antibodies,particularly fully humanized monoclonal antibodies, including but notlimited to the antibodies described in PCT Publ. No. WO 03/002713, whichis incorporated herein in its entirety as to OPGL specific antibodiesand antibody related proteins, particularly those having the sequencesset forth therein, particularly, but not limited to, those denotedtherein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including the OPGLspecific antibodies having either the light chain of SEQ ID NO: 2 as setforth therein in FIG. 2 and/or the heavy chain of SEQ ID NO:4, as setforth therein in FIG. 4, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing Publication;

Myostatin binding proteins, peptibodies, and related proteins, and thelike, including myostatin specific peptibodies, particularly thosedescribed in US Publ. No. 2004/0181033 and PCT Publ. No. WO 2004/058988,which are incorporated by reference herein in their entiretyparticularly in parts pertinent to myostatin specific peptibodies,including but not limited to peptibodies of the mTN8-19 family,including those of SEQ ID NOS: 305-351, including TN8-19-1 throughTN8-19-40, TN8-19 con1 and TN8-19 con2; peptibodies of the mL2 family ofSEQ ID NOS: 357-383; the mL15 family of SEQ ID NOS: 384-409; the mL17family of SEQ ID NOS: 410-438; the mL20 family of SEQ ID NOS: 439-446;the mL21 family of SEQ ID NOS: 447-452; the mL24 family of SEQ ID NOS:453-454; and those of SEQ ID NOS: 615-631, each of which is individuallyand specifically incorporated by reference herein in their entiretyfully as disclosed in the foregoing publication;

IL-4 receptor specific antibodies, peptibodies, and related proteins,and the like, particularly those that inhibit activities mediated bybinding of IL-4 and/or IL-13 to the receptor, including those describedin PCT Publ. No. WO 2005/047331 or PCT Appl. No. PCT/US2004/03742 and inUS Publ. No. 2005/112694, which are incorporated herein by reference intheir entirety particularly in parts pertinent to IL-4 receptor specificantibodies, particularly such antibodies as are described therein,particularly, and without limitation, those designated therein: L1H1;L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1;L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12;L2H13; L2H14; L3H1; L4H1; L5H1; L6H1, each of which is individually andspecifically incorporated by reference herein in its entirety fully asdisclosed in the foregoing publication;

Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies,and related proteins, and the like, including but not limited to thosedescribed in U.S. Publ. No. 2004/097712A1, which is incorporated hereinby reference in its entirety in parts pertinent to IL1-R1 specificbinding proteins, monoclonal antibodies in particular, especially,without limitation, those designated therein: 15CA, 26F5, 27F2, 24E12,and 10H7, each of which is individually and specifically incorporated byreference herein in its entirety fully as disclosed in theaforementioned U.S. publication;

Ang2 specific antibodies, peptibodies, and related proteins, and thelike, including but not limited to those described in PCT Publ. No. WO03/057134 and U.S. Publ No. 2003/0229023, each of which is incorporatedherein by reference in its entirety particularly in parts pertinent toAng2 specific antibodies and peptibodies and the like, especially thoseof sequences described therein and including but not limited to: L1(N);L1(N) WT; L1(N) 1K WT; 2×L1(N); 2×L1(N) WT; Con4 (N), Con4 (N) 1K WT,2×Con4 (N) 1K; L1C; L1C 1K; 2×L1C; Con4C; Con4C 1K; 2×Con4C 1K; Con4-L1(N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N); TN8-14 (N); Con 1 (N),also including anti-Ang 2 antibodies and formulations such as thosedescribed in PCT Publ. No. WO 2003/030833 which is incorporated hereinby reference in its entirety as to the same, particularly Ab526; Ab528;Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546;A551; Ab553; Ab555; Ab558; Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK;AbG1D4; AbGC1E8; AbH1C12; Ab1A1; Ab1F; Ab1K, Ab1P; and Ab1P, in theirvarious permutations as described therein, each of which is individuallyand specifically incorporated by reference herein in its entirety fullyas disclosed in the foregoing publication;

NGF specific antibodies, peptibodies, and related proteins, and the likeincluding, in particular, but not limited to those described in US Publ.No. 2005/0074821 and U.S. Pat. No. 6,919,426, which are incorporatedherein by reference in their entirety particularly as to NGF-specificantibodies and related proteins in this regard, including in particular,but not limited to, the NGF-specific antibodies therein designated 4D4,4G6, 6H9, 7H2, 14D10 and 14D11, each of which is individually andspecifically incorporated by reference herein in its entirety fully asdisclosed in the foregoing publication;

CD22 specific antibodies, peptibodies, and related proteins, and thelike, such as those described in U.S. Pat. No. 5,789,554, which isincorporated herein by reference in its entirety as to CD22 specificantibodies and related proteins, particularly human CD22 specificantibodies, such as but not limited to humanized and fully humanantibodies, including but not limited to humanized and fully humanmonoclonal antibodies, particularly including but not limited to humanCD22 specific IgG antibodies, such as, for instance, a dimer of ahuman-mouse monoclonal hLL2 gamma-chain disulfide linked to ahuman-mouse monoclonal hLL2 kappa-chain, including, but limited to, forexample, the human CD22 specific fully humanized antibody inEpratuzumab, CAS registry number 501423-23-0;

IGF-1 receptor specific antibodies, peptibodies, and related proteins,and the like, such as those described in PCT Publ. No. WO 06/069202,which is incorporated herein by reference in its entirety as to IGF-1receptor specific antibodies and related proteins, including but notlimited to the IGF-1 specific antibodies therein designated L1H1, L2H2,L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12,L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21,L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30,L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39,L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48,L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments andderivatives thereof, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing International Publication;

Also among non-limiting examples of anti-IGF-1R antibodies for use inthe methods and compositions of the present invention are each and allof those described in:

-   (i) US Publ. No. 2006/0040358 (published Feb. 23, 2006),    2005/0008642 (published Jan. 13, 2005), 2004/0228859 (published Nov.    18, 2004), including but not limited to, for instance, antibody 1A    (DSMZ Deposit No. DSM ACC 2586), antibody 8 (DSMZ Deposit No. DSM    ACC 2589), antibody 23 (DSMZ Deposit No. DSM ACC 2588) and antibody    18 as described therein;-   (ii) PCT Publ. No. WO 06/138729 (published Dec. 28, 2006) and WO    05/016970 (published Feb. 24, 2005), and Lu et al., 2004, J Biol.    Chem. 279:2856-65, including but not limited to antibodies 2F8, A12,    and IMC-A12 as described therein;-   (iii) PCT Publ. No. WO 07/012614 (published Feb. 1, 2007), WO    07/000328 (published Jan. 4, 2007), WO 06/013472 (published Feb. 9,    2006), WO 05/058967 (published Jun. 30, 2005), and WO 03/059951    (published Jul. 24, 2003);-   (iv) US Publ. No. 2005/0084906 (published Apr. 21, 2005), including    but not limited to antibody 7C10, chimaeric antibody C7C10, antibody    h7C10, antibody 7H2M, chimaeric antibody *7C10, antibody GM 607,    humanized antibody 7C10 version 1, humanized antibody 7C10 version    2, humanized antibody 7C10 version 3, and antibody 7H2HM, as    described therein;-   (v) US Publ. Nos. 2005/0249728 (published Nov. 10, 2005),    2005/0186203 (published Aug. 25, 2005), 2004/0265307 (published Dec.    30, 2004), and 2003/0235582 (published Dec. 25, 2003) and Maloney et    al., 2003, Cancer Res. 63:5073-83, including but not limited to    antibody EM164, resurfaced EM164, humanized EM164, huEM164 v1.0,    huEM164 v1.1, huEM164 v1.2, and huEM164 v1.3 as described therein;-   (vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), US Publ. Nos.    2005/0244408 (published Nov. 30, 2005) and 2004/0086503 (published    May 6, 2004), and Cohen, et al., 2005, Clinical Cancer Res.    11:2063-73, e.g., antibody CP-751,871, including but not limited to    each of the antibodies produced by the hybridomas having the ATCC    accession numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789,    PTA-2793, and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and    4.17.3, as described therein;-   (vii) US Publ. Nos. 2005/0136063 (published Jun. 23, 2005) and    2004/0018191 (published Jan. 29, 2004), including but not limited to    antibody 19D12 and an antibody comprising a heavy chain encoded by a    polynucleotide in plasmid 15H12/19D12 HCA (γ4), deposited at the    ATCC under number PTA-5214, and a light chain encoded by a    polynucleotide in plasmid 15H12/19D12 LCF (κ), deposited at the ATCC    under number PTA-5220, as described therein; and-   (viii) US Publ. No. 2004/0202655 (published Oct. 14, 2004),    including but not limited to antibodies PINT-6A1, PINT-7A2,    PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1,    PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12,    PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4, and PINT-12A5, as    described therein; each and all of which are herein incorporated by    reference in their entireties, particularly as to the aforementioned    antibodies, peptibodies, and related proteins and the like that    target IGF-1 receptors;

B-7 related protein 1 specific antibodies, peptibodies, related proteinsand the like (“B7RP-1,” also is referred to in the literature as B7H2,ICOSL, B7h, and CD275), particularly B7RP-specific fully humanmonoclonal IgG2 antibodies, particularly fully human IgG2 monoclonalantibody that binds an epitope in the first immunoglobulin-like domainof B7RP-1, especially those that inhibit the interaction of B7RP-1 withits natural receptor, ICOS, on activated T cells in particular,especially, in all of the foregoing regards, those disclosed in U.S.Publ. No. 2008/0166352 and PCT Publ. No. WO 07/011941, which areincorporated herein by reference in their entireties as to suchantibodies and related proteins, including but not limited to antibodiesdesignated therein as follow: 16H (having light chain variable and heavychain variable sequences SEQ ID NO:1 and SEQ ID NO:7 respectivelytherein); 5D (having light chain variable and heavy chain variablesequences SEQ ID NO:2 and SEQ ID NO:9 respectively therein); 2H (havinglight chain variable and heavy chain variable sequences SEQ ID NO:3 andSEQ ID NO:10 respectively therein); 43H (having light chain variable andheavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14 respectivelytherein); 41H (having light chain variable and heavy chain variablesequences SEQ ID NO:5 and SEQ ID NO:13 respectively therein); and 15H(having light chain variable and heavy chain variable sequences SEQ IDNO:4 and SEQ ID NO:12 respectively therein), each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing U.S. Publication;

IL-15 specific antibodies, peptibodies, and related proteins, and thelike, such as, in particular, humanized monoclonal antibodies,particularly antibodies such as those disclosed in U.S. Publ. Nos.2003/0138421; 2003/023586; and 2004/0071702; and U.S. Pat. No.7,153,507, each of which is incorporated herein by reference in itsentirety as to IL-15 specific antibodies and related proteins, includingpeptibodies, including particularly, for instance, but not limited to,HuMax IL-15 antibodies and related proteins, such as, for instance,146B7;

IFN gamma specific antibodies, peptibodies, and related proteins and thelike, especially human IFN gamma specific antibodies, particularly fullyhuman anti-IFN gamma antibodies, such as, for instance, those describedin US Publ. No. 2005/0004353, which is incorporated herein by referencein its entirety as to IFN gamma specific antibodies, particularly, forexample, the antibodies therein designated 1118; 1118*; 1119; 1121; and1121*. The entire sequences of the heavy and light chains of each ofthese antibodies, as well as the sequences of their heavy and lightchain variable regions and complementarity determining regions, are eachindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing US Publication and inThakur et al., Mol. Immunol. 36:1107-1115 (1999). In addition,description of the properties of these antibodies provided in theforegoing US publication is also incorporated by reference herein in itsentirety. Specific antibodies include those having the heavy chain ofSEQ ID NO: 17 and the light chain of SEQ ID NO:18; those having theheavy chain variable region of SEQ ID NO:6 and the light chain variableregion of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 andthe light chain of SEQ ID NO:20; those having the heavy chain variableregion of SEQ ID NO:10 and the light chain variable region of SEQ IDNO:12; those having the heavy chain of SEQ ID NO:32 and the light chainof SEQ ID NO:20; those having the heavy chain variable region of SEQ IDNO:30 and the light chain variable region of SEQ ID NO:12; those havingthe heavy chain sequence of SEQ ID NO:21 and the light chain sequence ofSEQ ID NO:22; those having the heavy chain variable region of SEQ IDNO:14 and the light chain variable region of SEQ ID NO:16; those havingthe heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; andthose having the heavy chain variable region of SEQ ID NO:14 and thelight chain variable region of SEQ ID NO:31, as disclosed in theforegoing US Publication. A specific antibody contemplated is antibody1119 as disclosed in foregoing US Publication and having a completeheavy chain of SEQ ID NO:17 as disclosed therein and having a completelight chain of SEQ ID NO:18 as disclosed therein;

TALL-1 specific antibodies, peptibodies, and the related proteins, andthe like, and other TALL specific binding proteins, such as thosedescribed in U.S. Publ. Nos. 2003/0195156 and 2006/0135431, each ofwhich is incorporated herein by reference in its entirety as to TALL-1binding proteins, particularly the molecules of Tables 4 and 5B, each ofwhich is individually and specifically incorporated by reference hereinin its entirety fully as disclosed in the foregoing US Publications;

Parathyroid hormone (“PTH”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,756,480, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind PTH;

Thrombopoietin receptor (“TPO-R”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,835,809, which is herein incorporated by reference in its entirety,particularly in parts pertinent to proteins that bind TPO-R;

Hepatocyte growth factor (“HGF”) specific antibodies, peptibodies, andrelated proteins, and the like, including those that target theHGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human monoclonalantibodies that neutralize hepatocyte growth factor/scatter (HGF/SF)described in US Publ. No. 2005/0118643 and PCT Publ. No. WO 2005/017107,huL2G7 described in U.S. Pat. No. 7,220,410 and OA-5d5 described in U.S.Pat. Nos. 5,686,292 and 6,468,529 and in PCT Publ. No. WO 96/38557, eachof which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind HGF;

TRAIL-R2 specific antibodies, peptibodies, related proteins and thelike, such as those described in U.S. Pat. No. 7,521,048, which isherein incorporated by reference in its entirety, particularly in partspertinent to proteins that bind TRAIL-R2;

Activin A specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in US Publ. No.2009/0234106, which is herein incorporated by reference in its entirety,particularly in parts pertinent to proteins that bind Activin A;

PCSK9 (Proprotein Convertase Subtilisin/Kexin) specific antibodies,peptibodies, related proteins and the like including but not limited tothose described in U.S. Pat. No. 8,030,457, WO 11/0027287 and WO09/026558, which are herein incorporated by reference in their entirety,particularly in parts pertinent to proteins that bind PCSK9;

TGF-beta specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. Pat. No.6,803,453 and US Publ. No. 2007/0110747, each of which is hereinincorporated by reference in its entirety, particularly in partspertinent to proteins that bind TGF-beta;

Amyloid-beta protein specific antibodies, peptibodies, related proteins,and the like, including but not limited to those described in PCT Publ.No. WO 2006/081171, which is herein incorporated by reference in itsentirety, particularly in parts pertinent to proteins that bindamyloid-beta proteins. One antibody contemplated is an antibody having aheavy chain variable region comprising SEQ ID NO: 8 and a light chainvariable region having SEQ ID NO: 6 as disclosed in the InternationalPublication;

c-Kit specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in Publ. No. 2007/0253951,which is incorporated herein by reference in its entirety, particularlyin parts pertinent to proteins that bind c-Kit and/or other stem cellfactor receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. application Ser.No. 11/068,289, which is incorporated herein by reference in itsentirety, particularly in parts pertinent to proteins that bind OX40Land/or other ligands of the OXO40 receptor; and

Other exemplary proteins can include Activase® (alteplase, tPA);Aranesp® (darbepoetin alfa); Epogen® (epoetin alfa, or erythropoietin);Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonalantibody); Betaseron® (interferon-beta); Campath® (alemtuzumab,anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade®(bortezomib); MLN0002 (anti- a4137 mAb); MLN1202 (anti-CCR2 chemokinereceptor mAb); Enbrel® (etanercept, TNF-receptor/Fc fusion protein, TNFblocker); Eprex® (epoetin alfa); Erbitux® (cetuximab,anti-EGFR/HER1/c-ErbB-1); Genotropin® (somatropin, Human GrowthHormone); Herceptin® (trastuzumab, anti-HER2/neu (erbB2) receptor mAb);Humatrope® (somatropin, Human Growth Hormone); Humira® (adalimumab);insulin in solution; Infergen® (interferon alfacon-1); Natrecor®(nesiritide; recombinant human B-type natriuretic peptide (hBNP);Kineret® (anakinra); Leukine® (sargamostim, rhuGM-CSF); LymphoCide®(epratuzumab, anti-CD22 mAb); Benlysta™ (lymphostat B, belimumab,anti-BlyS mAb); Metalyse® (tenecteplase, t-PA analog); Mircera® (methoxypolyethylene glycol-epoetin beta); Mylotarg® (gemtuzumab ozogamicin);Raptiva® (efalizumab); Cimzia® (certolizumab pegol, CDP 870); Soliris™(eculizumab); pexelizumab (anti-CS complement); Numax® (MEDI-524);Lucentis® (ranibizumab); Panorex® (17-1A, edrecolomab); Trabio®(lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4);Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (visilizumab); cantuzumabmertansine (huC242-DM1); NeoRecormon® (epoetin beta); Neumega®(oprelvekin, human interleukin-11); Neulasta® (pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF); Neupogen® (filgrastim , G-CSF,hu-MetG-CSF); Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonalantibody); Procrit® (epoetin alfa); Remicade® (infliximab, anti-TNFαmonoclonal antibody); Reopro® (abciximab, anti-GP IIb/Ilia receptormonoclonal antibody); Actemra® (anti-IL6 Receptor mAb); Avastin®(bevacizumab), HuMax-CD4 (zanolimumab); Rituxan® (rituximab, anti-CD20mAb); Tarceva® (erlotinib); Roferon-A®-(interferon alfa-2a); Simulect®(basiliximab); Prexige® (lumiracoxib); Synagis® (palivizumab); 146B7-CHO(anti-IL15 antibody, see U.S. Pat. No. 7,153,507); Tysabri®(natalizumab, anti-α4integrin mAb); Valortim® (MDX-1303, anti-B.anthracis protective antigen mAb); ABthrax™; Vectibix® (panitumumab);Xolair® (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (the Fc portionof human IgG1 and the extracellular domains of both IL-1 receptorcomponents (the Type I receptor and receptor accessory protein)); VEGFtrap (Ig domains of VEGFR1 fused to IgG1 Fc); Zenapax® (daclizumab);Zenapax® (daclizumab, anti-IL-2Rα mAb); Zevalin® (ibritumomab tiuxetan);Zetia® (ezetimibe); Orencia® (atacicept, TACI-Ig); anti-CD80 monoclonalantibody (galiximab); anti-CD23 mAb (lumiliximab); BR2-Fc (huBR3/huFcfusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNFαmAb); HGS-ETR1 (mapatumumab; human anti-TRAIL Receptor-1 mAb);HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (zalutumumab);M200 (volociximab, anti-α5β1 integrin mAb); MDX-010 (ipilimumab,anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-C. difficileToxin A and Toxin B C mAbs MDX-066 (CDA-1) and MDX-1388); anti-CD22dsFv-PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC);anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333(anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb; anti-CriptomAb; anti-CTGF Idiopathic Pulmonary Fibrosis Phase I Fibrogen (FG-3019);anti-CTLA4 mAb; anti-eotaxinl mAb (CAT-213); anti-FGF8 mAb;anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb(MYO-029); anti-GM-CSF Receptor mAb (CAM-3001); anti-HepC mAb (HuMaxHepC); anti-IFNα mAb (MEDI-545, MDX-1103); anti-IGF1R mAb; anti-IGF-1RmAb (HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12/IL23 mAb (CNTO1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC); anti-IL5Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO 95); anti-IP10Ulcerative Colitis mAb (MDX-1100); anti-LLY antibody; BMS-66513;anti-Mannose Receptor/hCGβ mAb (MDX-1307); anti-mesothelin dsFv-PE38conjugate (CAT-5001); anti-PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFRαantibody (IMC-3G3); anti-TGFβ mAb (GC-1008); anti-TRAIL Receptor-2 humanmAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb; anti-ZP3 mAb(HuMax-ZP3); NVS Antibody #1; and NVS Antibody #2.

We claim:
 1. A method of assembling an injector, the method comprising:providing a container having a wall defining an interior surface and aseal assembly, the wall and seal assembly defining a reservoir;providing a fluid delivery system physically separate from thecontainer, the fluid delivery system comprising a container needlehaving a point; sterilizing the container including the reservoir andfluid delivery system while the container and the fluid delivery systemare separate from each other; filling the reservoir of the containerwith a volume of a drug product under sterile conditions; after fillingthe reservoir of the container, attaching the fluid delivery system tothe filled container under clean room conditions such that the point ofthe container needle is disposed adjacent to the seal assembly to definea storage state; and attaching the container needle to an actuator, theactuator adapted to move the container needle from the storage state toa delivery state wherein the container needle is disposed through theseal assembly, into the reservoir, and in fluid communication with thedrug product for delivery to a patient.
 2. The method of claim 1,wherein filling the reservoir with a volume of a drug product comprisesfilling the reservoir with a volume of a PCSK9 (Proprotein ConvertaseSubtilisin/Kexin Type 9)-specific antibody or a granulocytecolony-stimulating factor (G-CSF).
 3. The method of claim 1, furthercomprising attaching a stopper to the container after filling thereservoir, thereby sealing the filled reservoir.
 4. The method of claim1, wherein attaching the fluid delivery system to the filled containercomprises attaching the container needle such that the container needledoes not penetrate a wall of the seal assembly.
 5. The method of claim1, wherein sterilizing the container comprises a radiation sterilizationtreatment and/or a gaseous sterilization treatment.
 6. The method ofclaim 1, wherein filling the reservoir of the container includes fillingthe reservoir in a space operated as an aseptic Class 100 clean room. 7.The method of claim 3, wherein attaching the stopper to the containerincludes attaching the stopper to the container in a space operated asan aseptic Class 100 clean room.
 8. The method of claim 1, prior toattaching the fluid delivery system to the container, inspecting thefilled container in a space operated as an aseptic Class 10,000 cleanroom.
 9. The method of claim 1, prior to attaching the fluid deliverysystem to the container, moving the filled container to an assemblyspace operated as an aseptic Class 10,000 clean room.
 10. The method ofclaim 1, further comprising swabbing a surface of the seal assemblyprior to attaching the fluid delivery system.
 11. The method of claim 1,wherein the reservoir of the container is filled in a first assemblyspace, and the fluid delivery system is attached to the filled containerin a second assembly space, wherein the second assembly space has alower level of cleanliness than the first assembly space.
 12. A methodof assembling an injector, the method comprising: providing a containerhaving a wall defining an interior surface and a seal assembly, the walland seal assembly defining a reservoir; providing a fluid deliverysystem physically separate from the container, the fluid delivery systemcomprising a container needle having a point; sterilizing the containerincluding the reservoir and fluid delivery system while the containerand the fluid delivery system are separate from each other; filling thereservoir of the container with a volume of a drug product under sterileconditions; attaching the fluid delivery system to the filled containerunder clean room conditions such that the point of the container needleis disposed within the seal assembly to define a storage state; andattaching the container needle to an actuator, the actuator adapted tomove the container needle from the storage state to a delivery statewherein the container needle is disposed through the seal assembly, intothe reservoir, and in fluid communication with the drug product fordelivery to a patient.
 13. The method of claim 12, wherein filling thereservoir with a volume of a drug product comprises filling thereservoir with a volume of a PCSK9 (Proprotein ConvertaseSubtilisin/Kexin Type 9)-specific antibody or a granulocytecolony-stimulating factor (G-CSF).
 14. The method of claim 12, furthercomprising attaching a stopper to the container after filling thereservoir, thereby sealing the filled reservoir.
 15. The method of claim12, wherein sterilizing the container comprises a radiationsterilization treatment and/or a gaseous sterilization treatment. 16.The method of claim 12, wherein filling the reservoir of the containerincludes filling the reservoir in a space operated as an aseptic Class100 clean room.
 17. The method of claim 14, wherein attaching thestopper to the container includes attaching the stopper to the containerin a space operated as an aseptic Class 100 clean room.
 18. The methodof claim 12, prior to attaching the fluid delivery system to thecontainer, moving the filled container to an assembly space operated asan aseptic Class 10,000 clean room.
 19. The method of claim 12, whereinthe reservoir of the container is filled in a first assembly space, andthe fluid delivery system is attached to the filled container in asecond assembly space, wherein the second assembly space has a lowerlevel of cleanliness than the first assembly space.
 20. The method ofclaim 12, wherein: a seal assembly includes a first wall and a secondwall, the reservoir is defined at least by the interior surface of thewall of the container and a first surface of the first wall of the sealassembly, an enclosed clean space is defined at least by a secondsurface of the wall of the seal assembly and the second wall of the sealassembly, and the point of the container needle is disposed through thesecond wall of the seal assembly into the enclosed space in the storagestate and disposed through the first wall of the seal assembly into thereservoir in the delivery state.